The human IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, his group discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans; in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID; and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in this lab and others, gc was shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Work on the identification of genes induced or repressed by IL-2 and related cytokines has continued and some of these are being characterized. A study on IL-2-mediated repression of IL-7 receptor alpha chain expression was accepted, a finding with potential major implications in understanding how IL-2 can promote cell death as well as repression. The mechanism of IL-7-mediated repression depends on PI 3-kinase and Akt. Other aspects of IL-2 signaling, particularly IL-2-induced serine phosphorylation are being studied, and a major serine phosphorylation site of Stat5a was identified and a manuscript was accepted for publication. Interesting, this phosphorylation did not exert a positive effect as has been found for other STAT proteins; instead, if anything, the effect could be negative. Having reported the previous year the cDNA cloning of a novel type I cytokine receptor protein which was demonstrated to be the receptor for thymic stromal lymphopoietin (TSLP), the group has worked to create a TSLPR KO mouse. The cloning of another novel cytokine receptor, now denoted as the IL-21 receptor, was previously published, creating a new field. It was previously shown that the IL-21 receptor was restricted to lymphoid cells, with expression on T-cells, NK-cells, and B-cells and that the receptor utilized the Jak-STAT pathway. In the past year, major advances were made in studying the effect of this protein in vivo, demonstrating that it plays a criical role in immunoglobulin biosynthesis. Its function in vivo is being further studied. Overall, these studies help to aspects of signaling by IL-2 and related cytokines. These findings have relevance to immunodeficiency and the control of T-cell growth.